Pharmacological Profile of AZD8871 (LAS191351), a Novel Inhaled Dual M3 Receptor Antagonist/β2-Adrenoceptor Agonist Molecule with Long-Lasting Effects and Favorable Safety Profile

AZD8871 is a novel muscarinic antagonist and beta(2)-adrenoceptor agonist in development for chronic obstructive pulmonary disease. This study describes the pharmacological profile of AZD8871 in in vitro and in vivo assays. AZD8871 is potent at the human M-3 receptor (pIC(50) in binding assays: 9.5) and shows kinetic selectivity for the M-3 (half-life: 4.97 hours) over the M-2 receptor (half-life: 0.46 hour). It is selective for the beta(2)-adrenoceptor over the beta(1) and beta(3) subtypes (3- and 6-fold, respectively) and shows dual antimuscarinic and beta(2)-adrenoceptor functional activity in isolated guinea pig tissue (pIC(50) in electrically stimulated trachea: 8.6; pEC(50)( )in spontaneous tone isolated trachea: 8.8, respectively), which are sustained over time. AZD8871 exhibits a higher muscarinic component than batefenterol in human bronchi, with a shift in potency under propranolol blockade of 2- and 6-fold, respectively, together with a persisting relaxation (5.3% recovery at 8 hours). Nebulized AZD8871 prevents acetylcholine-induced bronchoconstriction in both guinea pig and dog with minimal effects on salivation and heart rate at doses with bronchoprotective activity. Moreover, AZD8871 shows long-lasting effects in dog, with a bronchoprotective half-life longer than 24 hours. In conclusion, these studies demonstrate that AZD8871 is a dual-acting molecule with a high muscarinic component and a long residence time at the M-3 receptor; moreover, its preclinical profile in animal models suggests a once-daily dosing in humans and a favorable safety profile. Thus, AZD8871 has the potential to be a next generation of inhaled bronchodilators in respiratory diseases.